For improvement of bioavailability of an active ingredient of a pharmaceutical product and the like, various pharmaceutical contrivances have been made so far. For example, Japanese Patent Unexamined Publication (KOKAI) No. 2004-99442 describes a method of preparing microparticles of a hardly soluble drug substance having a mean particle diameter of several hundreds nanometers by dry grinding of a mixture of the hardly soluble drug substance, polyvinylpyrrolidone, and sodium dodecylsulfate. However, in order to prepare microparticles having a mean particle diameter of several hundreds nanometers, a special grinder or grinding process may be required, and moreover, microparticles of the aforementioned level have drawbacks in handling, for example, they are hardly wetted with water, and they coagulate in an aqueous medium. Further, the aforementioned publication fails to disclose an oily suspension of an active ingredient.
Japanese Patent Unexamined Publication No. 2005-112753 describes that, as for a soft capsule in which an active ingredient is suspended in an oil or a fat, bioavailability can be improved by further adding a hydrogenated oil or a fat to the content. However, this publication is totally silent about correlation of mean particle diameter of the active ingredient and bioavailability thereof in the oily suspension preparations.
Japanese Patent Unexamined Publication No. 7-138151 discloses a soft capsule containing 5 to 40 mass % of a powdered raw material that is hardly soluble in an oil and 60 to 95 mass % of an oil-soluble raw material. The aforementioned publication describes values of 0.1 nm to 1 mm as a mean particle diameter of the hardly oil-soluble powdered raw material in paragraph [0008]. The pharmaceutical preparation disclosed in the publication is explained to achieve simultaneous high-dose intake of the hardly oil-soluble powdered raw material and the oil-soluble raw material, however, a purpose of providing the preparation is not improvement in bioavailability of an active ingredient. Further, this publication is completely silent about correlation between a mean particle diameter of an active ingredient and bioavailability thereof.
International Publication WO2004/073692 describes in page 3, lines 29 to 39 that “there are recently marketed gelatin soft capsules containing about 15 mass % of ciclosporin as an immunosuppressant, a solubilizer, and a surfactant and having increased water solubility, no deposition in the gastrointestinal tract after oral administration, little fluctuation in oral absorption, and improved oral absorption (Neoral (registered trademark), Clin. Transplantation, Vol. 10, 364-373 (1996)), and sustained-release hard capsules encapsulating a semi-solid oily suspension matrix formed by simply suspending captopril in fat and oil (International Journal of Pharmaceutics, Vol. 41, 245-254 (1988))”. However, Neoral is a microemulsion preparation of which particle diameter is not larger than 0.15 μm, and is not an oily suspension of an active ingredient prepared as microparticles, and the aforementioned captopril hard capsules aim at sustained release, in which the active ingredient is not made into microparticles.
Further, Japanese Patent Unexamined Publication Nos. 10-81621, 11-302156, Japanese Patent Unexamined Publication based on PCT Application (KOHYO) Nos. 2000-516244, 2006-513267, and Japanese Patent Unexamined Republication based on PCT Application (SAIKOHYO) No. 2005-13938 describe a suspension of hardly water-soluble compounds made into microparticles. However, these publications do not include any specific description or examples concerning a process of suspending the hardly water-soluble compounds made into microparticles. Therefore, the aforementioned description of the term “suspension” in these publications is a mere general explanation, and is not described so as to be enabled.
Furthermore, Japanese Patent Unexamined Publication Nos. 6-16556, 2004-99442 and Japanese Patent Unexamined Publication based on PCT Application No. 2005-516943 include descriptions concerning aqueous suspensions of hardly water-soluble compounds made into microparticles. However, these publications neither suggest nor teach improvement of bioavailability by providing an oily suspension.
Japanese Patent Unexamined Publication based on PCT Application No. 2002-528492 discloses that bioavailability of isotretinoin, which is used for treatment of resistant cystic acne, is improved by subjecting an oily suspension of isotretinoin, per se, having a mean particle diameter of about 90 to 100 μm to a microparticle forming operation to obtain a mean particle diameter of 5 to 30 μm. Further, Japanese Patent Unexamined Publication No. 2007-039408 describes a method of preparing microparticle creatine having a mean particle diameter of 2 μm or smaller by dispersing creatine in a non-aqueous solvent (ethanol) and then performing grinding in a bead mill. However, although these two publications teach that bioavailability is improved by making particle diameter smaller, they do not suggest nor teach that, by making a drug substance into microparticles and forming an oily suspension of the microparticles, higher bioavailability can be achieved compared with that obtainable by simply making the drug substance into microparticles.
IBD (Inflammatory Bowel Disease) is a general term referring to Crohn's disease and ulcerative colitis, and both of the two diseases are intractable diseases which recurs and abates repeatedly. Since acceleration of immune functions and increase of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and an interleukin-1 (IL-1) are observed in pathological conditions of IBD, inhibition of the p38MAP kinase, which locates upstream of these inflammatory cytokines or the inflammatory reaction pathways thereof, is expected to be effective for therapeutic treatment of IBD (see, for example, J. Pharmacol. Exp. Ther., 284, 687-692 (1998); N. Engl. J. Med., 337, 1029-1035 (1997); Gut., 40, 628-633 (1997)).
As compounds having a p38MAP kinase inhibitory action, there are so far known, for example, imidazole derivatives (see, Bioorganic & Medicinal Chemistry, Vol. 5, No. 1, 49-64 (1997), WO93/14081), pyrazole derivatives (see, WO98/52940, WO00/39116), isoxazole derivatives (see, Japanese Patent Unexamined Publication No. 2000-86657, WO96/25405, WO2004/17968, WO2004/22555, WO2006/070927), thiazole derivatives (see, WO00/64894), triazolopyridine derivatives (see WO2004/72072), pyridopyrimidine derivatives (see, WO2004/14907), naphthylidine derivatives (see, WO2004/73628), 6-membered condensed pyrazole derivatives (see, WO2005/73189, WO2005/85249), bicyclic hetero aromatic ring compound (see, WO2004/00846), and the like. However, no p38MAP kinase inhibitor as a pharmaceutical product has yet been launched into the market.
From a viewpoint of the mechanism of action, p38MAP kinase inhibitors has been developed mainly for systemic inflammatory diseases such as rheumatism as indications thereof. However, p38MAP kinase inhibitors have many problems such as distribution into the central nervous system, hepatotoxicity, and nephrotoxicity, and therefore, the inhibitor was found to be difficult to be developed as a pharmaceutical product for treatments of the diseases by maintaining a constant blood level. However, p38MAP kinase inhibitors may possibly be suitable for local inflammatory diseases such as IBD, and therefore, development of therapeutic agent for IBD is expected which acts locally such as in the intestinal tract.